The present invention relates generally to isomeric fused pyrrolocarbazoles and isoindolones, including pharmaceutical compositions, diagnostic kits, assay standards or reagents containing the same, and methods of using the same as therapeutics. The invention is also directed to intermediates and processes for making these novel compounds.
The microbial-derived material referred to as xe2x80x9cK-252axe2x80x9d is a unique compound which has gained significant attention over the past several years due to the variety of functional activities which it possesses. K-252a is an indolocarbazole alkaloid that was originally isolated from a Nocardiosis sp. culture (Kase, H et al. 39 J. Antibiotics 1059, 1986). K-252a is an inhibitor of several enzymes, including protein kinase C (PKC) which plays a central role in regulating cell functions, and trk tyrosine kinase. The reported functional activities of K-252a and its derivatives are numerous and diverse: tumor inhibition (See U.S. Pat. Nos. 4,877,776, 4,923,986, and 5,063,330; European Publication 238,011 in the name of Nomato); anti-insecticidal activity (See U.S. Pat. No. 4,735,939); inhibition of inflammation (See U.S. Pat. No. 4,816,450); treatment of diseases associated with neuronal cells (See U.S. Pat. Nos. 5,461,146; 5,621,100; 5,621,101; and WIPO Publication WO 94/02488, published Feb. 3, 1994 in the names of Cephalon, Inc. and Kyowa Hakko Kogyo Co., Ltd); and treatment of prostate disease (See U.S. Pat. Nos. 5,516,771; and 5,654,427). K-252a also has been reported to inhibit IL-2 production (See Grove, D. S. et al., Experimental Cell Research 193: 175-182, 1991).
The reported indolocarbazoles share several common attributes. In particular, each comprises three five member rings which all include a nitrogen moiety; staurosporine (derived from Streptomyces sp.) and K-252a each further comprise a sugar moiety linked via two N-glycosidic bonds. Both K-252a and staurosporine have been extensively studied with respect to their utility as therapeutic agents. The indolocarbazoles are generally lypophilic, which allows for their comparative ease in crossing biological membranes, and, unlike proteinaceous materials, they manifest a longer in vivo half-life.
Although K-252a is normally derived from culture media via a fermentation process, the total synthesis of the natural (+) isomer and the unnatural (xe2x88x92) isomer, in which the three chiral carbons of the sugar have the opposite configurations, has been achieved (See Wood et al., J. Am. Chem. Soc. 117:10413, 1995, and WIPO Publication WO 97/07081). However, this synthesis is not practical for commercial use.
In addition to the indolocarbazole alkaloids represented by K-252a and staurosporine, synthetic small organic molecules which are biologically active and known as fused pyrrolocarbazoles have been prepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; 5,705,511; and 5,616,724).
Fused isoindolones which are non-indole-containing molecules that can be chemically synthesized de novo are also known (See U.S. Pat. No. 5,808,060 and WIPO Publication WO 97/21677). Certain bis-indolylmaleimide macrocyclic derivatives have also been reported (See for example U.S. Pat. Nos. 5,710,145; 5,672,618; 5,552,396 and 5,545,636). Sugar derivatives of indolopyrrolocarbazoles also have been reported (see WIPO Publication WO98/07433). There remains a need for novel pyrrolocarbazole and isoindolone derivatives that possess beneficial properties. This invention is directed to this, as well as other, important ends.
Accordingly, one object of the present invention is to provide novel compounds which are kinase inhibitors. Particularly, the compounds of the present invention are inhibitors of trk kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth factor receptor (VEGFR) kinase, or NGF-stimulated trk phosphorylation. Another object of the invention is to provide novel compounds which enhance the trophic factor-induced activities of trophic factor responsive cells.
It is another object of the present invention to provide pharmaceutical compositions having activity toward trk kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth factor receptor (VEGFR) kinase, NGF-stimulated trk phosphorylation, or tropic factor responsive cells wherein the composition comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt form thereof
It is another object of the present invention to provide a novel method for treating or preventing disorders associated with the aberrant activity of trk kinase, platelet derived growth factor receptor PDGFR) kinase, vascular endothelial growth factor receptor (VEGFR) kinase, NGF-stimulated trk phosphorylation, or tropic factor responsive cells, wherein the method comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of at least one of the compounds of the present invention.
It is another object of the present invention to provide a method for inhibiting trk kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth factor receptor (VEGFR) kinase, NGF-stimulated trk phosphorylation, or enhancing tropic factor responsive cell activity, in a body fluid sample wherein the method comprises treating the body fluid sample with an effective amount of at least one of the compounds of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a diagnostic, standard or reagent.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor""s discovery that compounds of Formula I: 
stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, wherein A, B, C, D, E, F, G, Q, X, W, Y, R2, R3, R4, and R5 are defined below, are effective kinase inhibitors.
Thus, in a first embodiment, the present invention provides a novel compound of Formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring D is selected from phenyl and cyclohexene with double bond a-b;
ring B and ring F, independently, and each together with the carbon atoms to which they are attached, are selected from:
a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms may be replaced by hetero atoms; and
b) a 5-membered carbocyclic ring in which either
1) one carbon atom may be replaced with an oxygen, nitrogen, or sulfur atom;
2) two carbon atoms may be replaced with a sulfur and a nitrogen atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
3) three carbon atoms may be replaced with three nitrogen atoms, one oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
Gxe2x80x94Xxe2x80x94W is selected from:
a) xe2x80x94(A1A2)Cxe2x80x94N(R1)xe2x80x94C(B1B2)xe2x80x94;
b) xe2x80x94CH(R1A)xe2x80x94C(xe2x95x90O)xe2x80x94N(R1)xe2x80x94; and
c) xe2x80x94N(R1)xe2x80x94C(xe2x95x90O)xe2x80x94CH(R1A)xe2x80x94;
R1 is selected from:
a) H, substituted or unsubstituted alkyl of 1 to 6 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl;
b) xe2x80x94C(xe2x95x90O)R7, where R7 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic group, and substituted or unsubstituted heterocyclyl groups;
c) xe2x80x94OR8, where R8 is selected from H and alkyl having from 1 to 6 carbons;
d) xe2x80x94C(xe2x95x90O)NHR8, xe2x80x94NR9R10, xe2x80x94(CH2)pNR9R10, xe2x80x94(CH2)pOR8, xe2x80x94O(CH2)pOR8 and xe2x80x94O(CH2)pNR9R10, where p is from 1 to 4; and where either
1) R9 and R10 are each independently selected from H, unsubstituted alkyl of 1 to 6 carbons, and substituted alkyl; or
2) R9 and R10 together form a linking group of the formula xe2x80x94(CH2)2xe2x80x94X1xe2x80x94(CH2)2xe2x80x94, wherein X1 is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94CH2xe2x80x94;
R1A is the same as R1;
R2, R3, R4and R5 are each independently selected from:
a) H, aryl, carbocyclyl, heterocyclyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR7, Br, I xe2x80x94O(CH2)pNR9R10, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NR9R10, xe2x80x94O(CH2)pOR8, F, Cl, xe2x80x94CH2OR8, xe2x80x94NR9R10, xe2x80x94NR8S(xe2x95x90O)2R7, xe2x80x94NR8C(xe2x95x90O)R7, or xe2x80x94NR8C(xe2x95x90S)R7;
b) xe2x80x94CH2OR11, where R11 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
c) xe2x80x94NR8C(xe2x95x90O)NR9R10, xe2x80x94NR8C(xe2x95x90S)NR9R10, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R12, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94C(xe2x95x90S)NR9R10, xe2x80x94CHxe2x95x90NOR12, xe2x80x94CHxe2x95x90NR7, xe2x80x94(CH2)pNR9R10, xe2x80x94(CH2)pNHR11, or xe2x80x94CHxe2x95x90NNR12R12A; where
R12 is selected from H, alkyl of 1 to 6 carbons, xe2x80x94OH, alkoxy of 1 to 6 carbons, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90S)NR9R10, xe2x80x94O(CH2)pNR9R10, xe2x80x94O(CH2)pOR8, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, substituted or unsubstituted heterocyclylalkyl, and a substituted or unsubstituted carbocyclic group;
R12A is the same as R12;
d) xe2x80x94S(O)yR12, xe2x80x94(CH2)pS(O)yR7, xe2x80x94CH2S(O)yR11 where y is 0, 1 or 2;
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, and alkynyl of 2 to 8 carbons, wherein:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3 groups selected from aryl of 6 to 10 carbons, heterocyclyl, arylalkoxy, heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR7, xe2x80x94X2(CH2)pC(xe2x95x90O)NR9R10, xe2x80x94X2(CH2)pC(xe2x95x90S)NR9R10, xe2x80x94X2(CH2)pOC(xe2x95x90O)NR9R10, xe2x80x94X2(CH2)pCO2R7, xe2x80x94X2(CH2)pS(O)yR7, xe2x80x94X2(CH2)pNR8C(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NHR12, O-tetrahydropyranyl, xe2x80x94NR9R10, xe2x80x94NR8CO2R7, xe2x80x94NR8C(xe2x95x90O)NR9R10, xe2x80x94NR8C(xe2x95x90S)NR9R10, xe2x80x94NHC(xe2x95x90NH)NH2, xe2x80x94NR8C(xe2x95x90O)R7, xe2x80x94NR8C(xe2x95x90S)R7, xe2x80x94NR8S(xe2x95x90O)2R7, xe2x80x94S(O)yR7, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94C(xe2x95x90S)NR9R10, xe2x80x94C(xe2x95x90O)R12, xe2x80x94CH2OR8, xe2x80x94CHxe2x95x90NNR12R12A, xe2x80x94CHxe2x95x90NOR12, xe2x80x94CHxe2x95x90NR7, xe2x80x94CHxe2x95x90NNHCH(Nxe2x95x90NH)NH2, xe2x80x94S(xe2x95x90O)2NR12R12A, xe2x80x94P(xe2x95x90O)(OR8)2, xe2x80x94OR11, and a monosaccharide of 5 to 7 carbons where each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl of 1 to 4 carbons, alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons;
X2 is O, S, or NR8;
Q is selected from xe2x80x94NR6, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94;
R6 is selected from H, xe2x80x94SO2R7, xe2x80x94CO2R7, xe2x80x94C(xe2x95x90O)R7, xe2x80x94C(xe2x95x90O)NR9R10, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group independently is substituted, as defined for R2, R3, R4, and R5 in e) above;
Y is selected from:
a) an unsubstituted alkylene of 1-3 carbons;
b) an alkylene of 1-3 carbons substituted with R13, where R13 is selected from R12, thioalkyl of 1-4 carbons, halogen, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons, where
i) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons is unsubstituted; or
ii) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons, independently, is substituted, as defined for R2, R3, R4, and R5 in e) above; and
c) a functional group selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH(OH)xe2x80x94CH(OH)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94C(R6)2xe2x80x94, xe2x80x94Cxe2x95x90C(R13)2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR12)xe2x80x94, xe2x80x94C(OR12)R12xe2x80x94, xe2x80x94C(xe2x95x90O)CH(R6)xe2x80x94, xe2x80x94CH(R6)C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR12)CH(R6)xe2x80x94, xe2x80x94CHR8C(xe2x95x90NOR12)xe2x80x94, xe2x80x94C(xe2x95x90O)N(R8)xe2x80x94, xe2x80x94N(R8)C(xe2x95x90O)xe2x80x94, xe2x80x94CH2Zxe2x80x94, xe2x80x94ZCH2xe2x80x94, and xe2x80x94CH2ZCH2xe2x80x94, where Z is selected from xe2x80x94C(R12)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90NOR12)xe2x80x94, and xe2x80x94N(R12)xe2x80x94;
A1 and A2 are selected from H, H; H, OR12; H, xe2x80x94SR12; H, xe2x80x94N(R12)2; and a group where A1 and A2 together form a moiety selected from xe2x95x90O, xe2x95x90S, and xe2x95x90NR12; and,
B1 and B2 are selected from H, H; H, xe2x80x94OR12; H, xe2x80x94SR12; H, xe2x80x94N(R12)2; and a group where B1 and B2 together form a moiety selected from xe2x95x90O, xe2x95x90S, and xe2x95x90NR12;
with the proviso that at least one of the pairs A1 and A2, or B1 and B2, form xe2x95x90O.
In another embodiment, the present invention provides a novel compound of Formula XXII: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring D is selected from phenyl and cyclohexene with double bond a-b;
ring B and ring F, independently, and each together with the carbon atoms to which they are attached, are selected from:
a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms may be replaced by hetero atoms; and
b) a 5-membered carbocyclic ring in which either
1) one carbon atom may be replaced with an oxygen, nitrogen, or sulfur atom;
2) two carbon atoms may be replaced with a sulfur and a nitrogen atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
3) three carbon atoms may be replaced with three nitrogen atoms, one oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
Gxe2x80x94Xxe2x80x94W is selected from:
a) xe2x80x94(A1A2)Cxe2x80x94N(R1)xe2x80x94C(B1B2)xe2x80x94;
b) xe2x80x94CH(R1A)xe2x80x94C(xe2x95x90O)xe2x80x94N(R1)xe2x80x94; and
c) xe2x80x94N(R1)xe2x80x94C(xe2x95x90O)xe2x80x94CH(R1A)xe2x80x94;
R1 is selected from:
a) H, substituted or unsubstituted alkyl of 1 to 6 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl;
b) xe2x80x94C(xe2x95x90O)R7, where R7 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbocyclic group, and substituted or unsubstituted heterocyclyl groups;
c) xe2x80x94OR8, where R8 is selected from H and alkyl having from 1 to 6 carbons;
d) xe2x80x94C(xe2x95x90O)NR8, xe2x80x94NR9R10, xe2x80x94(CH2)pNR9R10, xe2x80x94(CH2)pOR8, xe2x80x94O(CH2)pOR8 and xe2x80x94O(CH2)pNR9R10, where p is from 1 to 4; and where either
1) R9 and R10 are each independently selected from H, unsubstituted alkyl of 1 to 6 carbons, and substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or
2) R9 and R10 together form a linking group of the formula xe2x80x94(CH2)2xe2x80x94X1xe2x80x94(CH2)2xe2x80x94, wherein X1 is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94CH2xe2x80x94;
R1A is the same as R1;
R2, R3, R4 and R5 are each independently selected from:
a) H, aryl, carbocyclyl, heterocyclyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR7, Br, I, xe2x80x94O(CH2)pNR9R10, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NR9R10, xe2x80x94O(CH2)pOR8, F, Cl, xe2x80x94CH2OR8, xe2x80x94NR9R10, xe2x80x94NR8S(xe2x95x90O)R7, xe2x80x94NR8C(xe2x95x90O)R7, or xe2x80x94NR8C(xe2x95x90S)R7;
b) xe2x80x94CH2OR11, where R11 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
c) xe2x80x94NR8C(xe2x95x90O)NR9R10, xe2x80x94NR8C(xe2x95x90S)NR9R10, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R12, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94C(xe2x95x90S)NR9R10, xe2x80x94CHxe2x95x90NOR12, xe2x80x94CHxe2x95x90NR7, xe2x80x94(CH2)pNR9R10, xe2x80x94(CH2)pNHR11, or CHxe2x95x90NNR12R12A; where
R12 is selected from H, alkyl of 1 to 6 carbons, xe2x80x94OH, alkoxy of 1 to 6 carbons, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90S)NR9R10, xe2x80x94O(CH2)pNR9R10, xe2x80x94O(CH2)pOR8, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, substituted or unsubstituted heterocyclylalkyl, and a substituted or unsubstituted carbocyclic group;
R12A is the same as R12;
d) xe2x80x94S(O)yR12, xe2x80x94(CH2)pS(O)yR7, xe2x80x94CH2S(O)yR11 where y is 0, 1 or 2;
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, and alkynyl of 2 to 8 carbons, wherein:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3 groups selected from aryl of 6 to 10 carbons, heterocyclyl, arylalkoxy, heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR7, xe2x80x94X2(CH2)pC(xe2x95x90O)NR9R10, xe2x80x94X2(CH2)pC(xe2x95x90S)NR9R10, xe2x80x94X2(CH2)pOC(xe2x95x90O)NR9R10, xe2x80x94X2(CH2)pCO2R7, xe2x80x94OC(xe2x95x90O)R7, xe2x80x94OC(xe2x95x90O)NHR12, O-tetrahydropyranyl, xe2x80x94NR9R10, xe2x80x94NR8CO2R7, xe2x80x94NR8C(xe2x95x90O)NR9R10, xe2x80x94NR8C(xe2x95x90S)NR9R10, xe2x80x94NHC(xe2x95x90NH)NH2, xe2x80x94NR8C(xe2x95x90O)R7, xe2x80x94NR8C(xe2x95x90S)R7, xe2x80x94NR8S(xe2x95x90O)2R7, xe2x80x94S(O)yR7, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94C(xe2x95x90S)NR9R10, xe2x80x94C(xe2x95x90O)R12, xe2x80x94CH2OR8, xe2x80x94CHxe2x95x90NNR12R12A, xe2x80x94CHxe2x95x90NOR12, xe2x80x94CHxe2x95x90NR7, xe2x80x94CHxe2x95x90NNHCH(Nxe2x95x90NH)NH2, xe2x80x94S(xe2x95x90O)2NR12R12A, xe2x80x94P(xe2x95x90O)(OR8)2, xe2x80x94OR11, and a monosaccharide of 5 to 7 carbons where each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl of 1 to 4 carbons, alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons;
X2 is O, S, or NR8;
Q is selected from xe2x80x94NR6, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94;
R6 is selected from H, xe2x80x94SO2R7, xe2x80x94CO2R7, xe2x80x94C(xe2x95x90O)R7, xe2x80x94C(xe2x95x90O)NR9R10, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group independently is substituted, as defined for R2, R3, R4, and R5 in e) above;
Y is selected from:
a) an unsubstituted alkylene of 1-3 carbons;
b) an alkylene of 1-3 carbons substituted with R13, where R13 is selected from R12, thioalkyl of 1-4 carbons, halogen, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons, where
i) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons is unsubstituted; or
ii) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons, independently, is substituted, as defined for R2, R3, R4, and R5 in e) above; and
c) a functional group selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH(OH)xe2x80x94CH(OH)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94C(R6)2xe2x80x94, xe2x80x94Cxe2x95x90C(R13)2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Cxe2x95x90N(R13)xe2x80x94, xe2x80x94C(xe2x95x90NOR12)xe2x80x94, xe2x80x94C(OR12)R12xe2x80x94, xe2x80x94C(xe2x95x90O)CH(R6)xe2x80x94, xe2x80x94CH(R6)C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR12)CH(R6)xe2x80x94, xe2x80x94CHR8C(xe2x95x90NOR12)xe2x80x94, xe2x80x94C(xe2x95x90O)N(R8)xe2x80x94, xe2x80x94N(R8)C(xe2x95x90O)xe2x80x94, xe2x80x94CH2Zxe2x80x94, xe2x80x94ZCH2xe2x80x94, and xe2x80x94CH2ZCH2xe2x80x94, where Z is selected from xe2x80x94C(R12)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90NOR12)xe2x80x94, and xe2x80x94N(R12)xe2x80x94;
A1 and A2 are selected from H, H; H, OR12; H, xe2x80x94SR12; H, xe2x80x94N(R12)2; and a group where A1 and A2 together form a moiety selected from xe2x95x90O, xe2x95x90S, and xe2x95x90NR12; and,
B1 and B2 are selected from H H; H, xe2x80x94OR12; H, xe2x80x94SR12; H, xe2x80x94N(R12)2; and a group where B1 and B2 together form a moiety selected from xe2x95x90O, xe2x95x90S, and xe2x95x90NR12;
with the proviso that at least one of the pairs A1 and A2, or B1 and B2, form xe2x95x90O.
In certain preferred embodiments of the compounds of Formula I, R1, R3, and R5 are H. In certain further preferred embodiments, xe2x80x94Gxe2x80x94Xxe2x80x94Yxe2x80x94 is CH2N(R1)C(xe2x95x90O), C(xe2x95x90O)N(R1)CH2, or C(xe2x95x90O)N(R1)C(xe2x95x90O).
In other preferred embodiments, rings B and F, independently, are substituted or unsubstituted phenyl or pyridyl. In other preferred embodiments, Q is xe2x80x94NR6, wherein the referred values for R6 are H and substituted or unsubstituted lower alkyl. In certain further preferred embodiments, Y is an unsubstituted alkylene of 1-3 carbons, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94.
In other preferred embodiments, the isomeric fused pyrrolocarbazoles are represented by the formula: 
In certain further preferred embodiments, the isomeric fused pyrrolocarbazoles are represented by the formula: 
In certain preferred embodiments of these formula, R1, R3 and R5 are H. In other preferred embodiments, A1 and A2 are selected from H, H; H, OH; H, OCH3; H, xe2x80x94N(R12)2; or a group where A1 and A2 together form xe2x95x90O or xe2x95x90NR12; B1 and B2 are selected from H, H; H, OH; H, OCH3; H, xe2x80x94N(R12)2; or a group where B1 and B2 together form xe2x95x90O or xe2x95x90NR12; and R12 is H, methyl, ethyl, propyl, xe2x80x94OH, or methoxy. In other preferred embodiments, the referred values for R6 are H or substituted or unsubstituted lower alkyl. In other preferred embodiments, Y is an unsubstituted alkylene of 1-3 carbons, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94. Even further preferred embodiments are the compounds set forth in Tables 1 to 4.
In other embodiments, the present invention provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. In a preferred composition, the compound of Formula I is one set forth in Table 1, 2, 3, or 4.
In certain preferred pharmaceutical compositions, the composition is for inhibiting one or more of trk kinase activity, VEGFR kinase activity, or PDGFR activity wherein the composition comprises a compound of Formula I and a pharmaceutically acceptable carrier. In other preferred pharmaceutical compositions the composition is for enhancing tropic factor or spinal chord ChAT activity wherein the composition comprises a compound of Formula I and a pharmaceutically acceptable carrier.
In other preferred pharmaceutical compositions, the composition is for treating or preventing prostate disorders such as prostate cancer or benign prostate hyperplasia In other preferred pharmaceutical compositions, the composition is for treating or preventing angiogenic disorders such as cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular degeneration. In other preferred pharmaceutical compositions, the composition is for treating or preventing neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis. In other preferred pharmaceutical compositions, the composition is for treating or preventing Alzheimer""s disease, amyotrophic lateral sclerosis, Parkinson""s disease, stroke, ischaemia, Huntington""s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or injuries of the brain or spinal chord.
In other embodiments, the present invention provides a method for inhibiting trk kinase activity comprising providing a compound of Formula I in an amount sufficient to result in effective inhibition. In a preferred embodiment, the compound of Formula I is provided to treat inflammation. In another preferred embodiment, the trk kinase receptor is trk A.
In other embodiments, the present invention provides a method for treating or preventing prostate disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I. In a preferred embodiment, the prostate disorder is prostate cancer or benign prostate hyperplasia.
In other embodiments, the present invention provides a method for treating or preventing angiogenic disorders where VEGFR kinase activity contributes to pathological conditions, the method comprising providing a compound of Formula I in an amount sufficient to result in the vascular endothelial growth factor receptor being contacted with an effective inhibitory amount of the compound. In another embodiment, the present invention provides a method for treating or preventing angiogenic disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I. In a preferred embodiment, the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.
In other embodiments, the present invention provides a method for treating or preventing disorders where PDGFR activity contributes to pathological conditions, the method comprising providing a compound of Formula I in an amount sufficient to result in the platelet derived growth factor receptor being contacted with an effective inhibitory amount of the compound. In another embodiment, the present invention provides a method for treating or preventing pathological disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I. In preferred embodiments, the pathological disorder is neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.
In other embodiments, the present invention provides a method for treating disorders characterized by the aberrant activity of trophic factor responsive cells, the method comprising providing a compound of Formula I in an amount sufficient to result in the trophic factor cell receptor being contacted with an effective activity inducing amount of the compound. In preferred embodiments, the activity of the trophic factor responsive cells is ChAT activity. In another embodiment, the present invention provides a method for treating or preventing Alzheimer""s disease, amyotrophic lateral sclerosis, Parkinson""s disease, stroke, ischaemia, Huntington""s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I. The compounds represented by Formula I may also be referred to as Compound I, and the same applies to the compounds of other formula numbers.
Definitions
The following terms and expressions have the indicated meanings. As used herein xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent The present invention is directed only to stable compounds. As used herein, xe2x80x9csubstitutedxe2x80x9d is intended to indicate that one or more hydrogen atoms on the indicated atom is replaced with a selected group referred to herein as a xe2x80x9csubstituentxe2x80x9d, provided that the substituted atom""s valency is not exceeded, and that the substitution results in a stable compound.
As used herein, the term xe2x80x9calkylxe2x80x9d means a straight-chain, cyclic, or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, hexyl, octyl, cyclopropyl, and cyclopentyl. The alkyl moiety of alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups, has the same meaning as alkyl defined above. Lower alkyl groups, which are preferred, are alkyl groups as defined above which contain 1 to 4 carbons.
Alkyl groups and alkyl moieties contained within substituent groups such as aralkyl, alkoxy, arylalkoxy, hydroxyalkoxy, alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alkylthio, alkylcarbonyloxy, hydroxyalkyl and acyloxy groups may be substituted or unsubstituted. A substituted alkyl group has 1 to 3 independently-selected substituents, preferably hydroxy, lower alkoxy, lower alkoxy-alkoxy, substituted or unsubstituted arylalkoxy-lower alkoxy, substituted or unsubstituted heteroarylalkoxy-lower alkoxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocycloalkoxy, halogen, carboxyl, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane, dithione, furan, lactone, or lactam.
As used herein, the term xe2x80x9calkenylxe2x80x9d is intended to include straight-chain, cyclic, or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, 3-methylbutenyl, and cyclohexenyl groups. As used herein, the term xe2x80x9calkynylxe2x80x9d is intended to include straight-chain, cyclic, or branched hydrocarbon chains having at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, 3-methylbutynyl, and cyclohexynyl groups.
As used herein, the xe2x80x9cacylxe2x80x9d moiety of acyl-containing groups such as acyloxy groups is intended to include a straight-chain, branched, or cyclic alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or hexanoyl.
As used herein, the term xe2x80x9ccarbocyclicxe2x80x9d refers to cyclic groups in which the ring portion is composed solely of carbon atoms. These include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl. The terms xe2x80x9cheterocycloxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d refer to cyclic groups in which the ring portion includes at least one heteroatom such as O, N, or S. Heterocyclyl groups include heteroaryl and heteroalkyl groups.
As used herein the term xe2x80x9carylxe2x80x9d means an aromatic ring having 6 to 12 carbon atoms such as phenyl, biphenyl and naphthyl. Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups. The term xe2x80x9cheteroarylxe2x80x9d as used herein denotes an aryl group in which one or more ring carbon atoms is replaced by a hetero (i.e., non-carbon) atom such as O, N or S. Preferred heteroaryl groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolyl groups. The term xe2x80x9cheteroalkylxe2x80x9d denotes a cycloalkyl group in which one or more ring carbon atoms is replaced by hetero atoms such as O, N, or S.
As used herein, the term xe2x80x9caralkylxe2x80x9d (or xe2x80x9carylalkylxe2x80x9d) is intended to denote a group having from 7 to 15 carbons, consisting of an alkyl group that bears an aryl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, benzhydryl and naphthylmethyl groups. Substituted aryl, substituted heterocyclic and substituted aralkyl groups each have 1 to 3 independently selected substituents that are preferably lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
Preferred heterocyclic groups formed with a nitrogen atom include pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, isoindolyl, imidazole, imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole, isothiazole, thiadiazoles, triazines, isoxazole, oxindole, indoxyl, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline, iosquinoline, and tetrazole groups. Preferred heterocyclic groups formed with an oxygen atom include furan, tetrahydrofuran, pyran, benzofurans, isobenzofurans, and tetrahydropyran groups. Preferred heterocyclic groups formed with a sulfur atom include thiophene, thianaphthene, tetrahydrothiophene, tetrahydrothiapyran, and benzothiophenes.
As used herein, xe2x80x9chydroxyalkylxe2x80x9d groups are alkyl groups that have a hydroxyl group appended thereto. As used herein, xe2x80x9chydroxyalkoxyxe2x80x9d groups are alkoxy groups that have a hydroxyl group appended thereto. As used herein, xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
As used herein, the term xe2x80x9cheteroarylalkylxe2x80x9d means an arylalkyl group that contains a heteroatom in the aryl moiety. The term xe2x80x9coxyxe2x80x9d denotes the presence of an oxygen atom. Thus, xe2x80x9calkoxyxe2x80x9d groups are alkyl groups that are attached through an oxygen atom, and xe2x80x9ccarbonyloxyxe2x80x9d groups are carbonyl groups that are attached through an oxygen atom.
As used herein, the terms xe2x80x9cheterocycloalkylxe2x80x9d and xe2x80x9cheterocycloalkoxyxe2x80x9d mean an alkyl or an alkoxy group that has a heterocyclo group attached to the alkyl moiety thereof, and the term xe2x80x9carylalkoxyxe2x80x9d means an alkoxy group that has an aryl group attached to the alkyl moiety thereof As used herein, the term xe2x80x9calkylcarbonyloxyxe2x80x9d means a group of formula xe2x80x94Oxe2x80x94C(xe2x95x90O)-alkyl.
As used herein, the term xe2x80x9calkyloxy-alkoxyxe2x80x9d denotes an alkoxy group that contains an alkyloxy substituent attached to its alkyl moiety. The term xe2x80x9calkoxy-alkylthioxe2x80x9d means an alkylthio group (i.e., a group of formula xe2x80x94S-alkyl) that contains an alkoxy substituent attached to its alkyl moiety. The term xe2x80x9chydroxy-alkylthioxe2x80x9d means an alkylthio group (i.e., a group of formula xe2x80x94S-alkyl) that contains a hydroxy substituent attached to its alkyl moiety.
As used herein, the term xe2x80x9cmonosaccharidexe2x80x9d has its accustomed meaning as a simple sugar. As used herein, the term xe2x80x9camino acidxe2x80x9d denotes a molecule containing both an amino group and a carboxyl group. Embodiments of amino acids include xcex1-amino acids; i.e., carboxylic acids of general formula HOOCxe2x80x94CH(NH2)-(side chain). Side chains of amino acids include naturally occurring and non-naturally occurring moieties. Non-naturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75, incorporated by reference herein. In certain embodiments, substituent groups for the compounds of Formulas I, II, and III include the residue of an amino acid after removal of the hydroxyl moiety of the carboxyl group thereof; i.e., groups of Formula xe2x80x94C(xe2x95x90O)CH(NH2)-(side chain).
Functional groups present on the compounds of Formula I may also contain protecting groups. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups may be found in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. Ed., Wiley and Sons, 1991, the disclosure of which is incorporated herein by reference.
As used herein, terms commonly used to describe the effects of therapeutic agents in biological systems, assays, and the like, are intended to have their art-recognized meanings. As used herein, the term xe2x80x9ceffectxe2x80x9d when used to modify the terms xe2x80x9cfunctionxe2x80x9d and xe2x80x9csurvivalxe2x80x9d means a positive or negative alteration or change. An effect which is positive may be referred to herein as an xe2x80x9cenhancementxe2x80x9d or xe2x80x9cenhancingxe2x80x9d, and an effect which is negative may be referred to herein as xe2x80x9cinhibitionxe2x80x9d or xe2x80x9cinhibiting.xe2x80x9d
As used herein, the terms xe2x80x9cenhancexe2x80x9d or xe2x80x9cenhancingxe2x80x9d when used to modify the terms xe2x80x9cfunctionxe2x80x9d or xe2x80x9csurvivalxe2x80x9d means that the presence of an isomeric fused pyrrolocarbazole or isoindolone compound has a positive effect on the function and/or survival of a trophic factor responsive cell compared with a cell in the absence of the compound. For example, and without limitation, with respect to the survival of, e.g., a cholinergic neuron, the compound would evidence enhancement of survival of a cholinergic neuronal population at risk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a cholinergic neuronal population not presented with such compound, if the treated population has a comparatively greater period of functionality than the non-treated population.
As used herein, xe2x80x9cinhibitxe2x80x9d and xe2x80x9cinhibitionxe2x80x9d mean that a specified response of a designated material (e.g., enzymatic activity) is comparatively decreased in the presence of an isomeric fused pyrrolocarbazole or isoindolone compound.
As used herein, the term xe2x80x9ctrkxe2x80x9d refers to the family of high affinity neurotrophin receptors presently comprising trk A, trk B, and trk C, and other membrane associated proteins to which a neurotrophin can bind.
As used herein, the terms xe2x80x9ccancerxe2x80x9d and xe2x80x9ccancerousxe2x80x9d refer to any malignant proliferation of cells in a mammal. Examples include prostate, benign prostate hyperplasia, ovarian, breast, brain, lung, pancreatic, colorectal, gastric, stomach, solid tumors, head and neck, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized malignancies of the hematopoietic systems, and other recognized cancers.
As used herein the terms xe2x80x9cneuron,xe2x80x9d xe2x80x9ccell of neuronal lineagexe2x80x9d and xe2x80x9cneuronal cellxe2x80x9d include, but are not limited to, a heterogeneous population of neuronal types having singular or multiple transmitters and/or singular or multiple functions; preferably, these are cholinergic and sensory neurons. As used herein, the phrase xe2x80x9ccholinergic neuronxe2x80x9d means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; exemplary are basal forebrain, striatal, and spinal cord neurons. As used herein, the phrase xe2x80x9csensory neuronxe2x80x9d includes neurons responsive to environmental cues (e.g., temperature, movement) from, e.g., skin, muscle and joints; exemplary is a neuron from the dorsal root ganglion.
As used herein, a xe2x80x9ctrophic factor-responsive cell,xe2x80x9d is a cell which includes a receptor to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic and sensory neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells).
As used herein, a xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount of a compound of the present invention effective to prevent or treat the symptoms of particular disorder. Such disorders include, but are not limited to, those pathological and neurological disorders associated with the aberrant activity of the receptors described herein, wherein the treatment or prevention comprises inhibiting, inducing, or enhancing the activity thereof by contacting the receptor with a compound of Formula I.
As used herein, the term xe2x80x9cpharmaceutically acceptablexe2x80x9d refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ration.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
As used herein, xe2x80x9cprodrugxe2x80x9d is intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention contemplates prodrugs of the claimed compounds, compositions containing the same, and methods of delivering the same. Prodrugs of a compound of the present invention, for example Formula I, may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
Synthesis
The compounds of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by the methods described below, or variations thereon as appreciated by the skilled artisan. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.
It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization; and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
As will be readily understood, functional groups present on the compounds of Formula I may contain protecting groups during the course of synthesis. For example, the amino acid side chain substituents of the compounds of Formula I can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the invention may be found in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis 2d. Ed., Wiley and Sons, 1991.
Compounds of the present invention may be prepared as outlined in the following schemes. Generally, imide compounds may be prepared as shown in Scheme 1. 
A cycloaddition reaction with maleimide and a cyclic-2-vinyl derivative (II) gives the tetrahydrocarbazole compounds of general structure (III), which can be dehydrogenated by methods well known in the art (Scheme 1). The cycloaddition reaction may be carried out in the absence of a solvent at temperatures of about 150 to about 200xc2x0 C., or in a solvent such as toluene, xylene or chlorobenzene at elevated temperatures with or without an added Lewis acid catalyst. The dienes of general structure (II) may be prepared by addition of a 2-lithio indole species, substituted or unsubstituted, to a cyclic (hetero)aryl 1-ketone, for example, 1-indanone, 1-tetralone, 4-chromanone, 4-keto-4,5,6,7-tetrahydrothianaphthlene, substituted or unsubstituted, as described, for example, in Tetrahedron Lett. 1985, 26, 5935, the disclosure of which is hereby incorporated by reference.
Scheme 2 outlines the general approach for preparing lactam isomers, i.e., compounds wherein Gxe2x80x94Xxe2x80x94W is xe2x80x94C(xe2x95x90O)xe2x80x94N(R1)xe2x80x94C(B1B2)xe2x80x94 or xe2x80x94C(A1A2)xe2x80x94N(R1)xe2x80x94C(xe2x95x90O)xe2x80x94. 
Cycloaddition reaction of dienes of general structure III with ethyl cis-xcex2-cyanoacrylate under conditions described for imides in Scheme 1 produces the cyanoester tetrahyrocarbazole regioisomers of general structures V and VI. Standard procedures such as recrystallization or chromatography may be used to separate the resulting regioisomers V and VI. The tetrahydrocarbazole cyano-esters may be readily dehydrogenated according to conventional processes with, for example, 2,3-dichloro-4,5-dicyano-1,4-benzoquinone to produce the aromatized carbazoles of general structure VII and VIII (Scheme 2). Lactams of general structure IX and X may be prepared separately or as a mixture by reductive cyclization of the nitrile-esters using reducing agents, for example, raney nickel/H2, PdO, and Pd or Pt on activated charcoal. The imide derivative IV may also be readily be reduced to lactam isomers IX and X by conventional processes such as zinc amalgam-HCl, Zn in acetic acid, or by treatment with hydride reducing agents such as lithium aluminum hydride. Standard processes such as recrystallization or chromatography may separate the resulting lactam regioisomers.
Compounds in which Gxe2x80x94Xxe2x80x94W is xe2x80x94CH(R1A)xe2x80x94C(xe2x95x90O)xe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94CH(R1A)xe2x80x94, as well as those in which Gxe2x80x94Xxe2x80x94W is a lactam or imide can be prepared by methods taught, for example, in U.S. Pat. Nos. 5,616,724, and 5,801,190, the disclosures of which is hereby incorporated herein by reference in its entirety. 
Compounds containing heteroaryl groups in rings B or F may be prepared using the described methods as demonstrated in Schemes 3 and 4. The phenyl ring of the indole may be a heterocycle, for example, but not limited to, 7-azaindole. 
Although the resulting alcohol derivative of general structure (I-i) shown in Scheme 1 may be dehydrated to compounds of general structure (II) using conditions known in the art such as HCl in acetone or p-toluenesulfonic acid in benzene, dienes of general structure (II) may be also be prepared using palladium catalyzed cross coupling methodology. For example, coupling an appropriate bromo, iodo or a trifluoromethane sulfonate derivative with a 2-stannyl- or 2-boronicacid indole derivative as shown in Scheme 5. 
The tetrahydrocarbazole cycloaddition adducts m can be readily dehydrogenated according to conventional processes with, for example, with 2,3-dichloro-4,5-dicyano-1,4-benzoquinone to give the aromatized carbazoles of general structure IV (Scheme 1). 
Scheme 6 outlines an alternative method to prepare lactam isomer of general structure X. A diene of general structure II, substituted or unsubstituted, is reacted with oxalyl chloride and an alcohol to produce keto-esters of general structure XIX. Olefination reactions known to those skilled in the art of organic synthesis, for example, reaction of ketone XIX with diethyl cyanomethylphosphonate, readily produces cyano-ester XX. Aromatic ring closure, under palladium catalyzed or oxidative conditions gives the cyano-ester carbazole of general structure XXI (Scheme 6) or VIII (Scheme 2). Reductive cyclization produces the lactam of general structure X (Scheme 2, 6).
Compounds of the present invention in which general structures IV, IX or X have Yxe2x95x90CH2 may be further substituted as shown in Scheme 7. 
Generally, compounds in which R6 is hydrogen, can be alkylated in the presence of base (e.g., hydrides, alkoxides, hydroxides of alkali or alkaline earth metals, or of organo-lithium compounds) by treatment with R6L in which L is a leaving group such as a halogen. The resulting pyrrolocarbazole may have an alkyl group, substituted or unsubstituted bound to the indole nitrogen, for example IV-20, 41. Compounds of general formula IV, IX or X, in which R6 is N-hydrogen may be subjected to Michael reaction conditions using a base, such as DBU and a Michael acceptor, such as an acrylic acid derivative or acrylonitrile to produce compounds IV-20-22. Reactions of this type may be further understood by reference to Scheme 8. 
Halo derivatives, such as bromine subsituted compound IV-9 may be used to further modify the indole ring as shown in Schemes 9 and 10. 
Palladium catalysed Heck reaction using IV-9 and a coupling partner such as a vinyl aryl or herteroaryl derivative, acrylic acid derivative or acrylonitrile produces vinyl derivatives IV-36, 37, 39, 43. The vinyl derivative may be reduced to the alkane derivatives such as IV-38, 40 using reducing conditions such as Palladium on carbon under a hydrogen atmosphere. 
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments. These examples are given for illustration of the invention and are not intended to be limiting thereof.